4-guanidinobutyramide for improving blood circulation

ABSTRACT

The subject invention pertains to methods of using 4-guanidinobutyramide, or a physiologically-acceptable salt thereof, in a mammal or human to improve blood circulation.

FIELD OF THE INVENTION

This invention relates to the regulation of blood flow in humanpatients. More particularly, it relates to the therapeutic use of aknown compound in the prevention and/or treatment of complicationsassociated with unsatisfactory circulation, e.g. of the type that areobserved in diabetics, although the treatment is also suitable fornon-diabetics.

BACKGROUND OF THE INVENTION

The compound 4-guanidinobutyramide (hereinafter "4GAB"), having theformula HN═C(NH₂)--NH--(CH₂)₃ --CONH₂, is a naturally-occurring compoundthat is known for therapeutic purposes. GB-A-1195199 and GB-A-1195200disclose 4GAB as a hypoglycaemic agent, the latter in combination withinsulin, for the treatment of diabetes. In U.S. Pat. No. 3,639,628, 4GABis shown to reduce abnormally high levels of blood urea in diabetics. Itis also stated that "improvements of retinopathy and neuropathy havebeen observed"; it has now been shown that 4GAB has little or no effecton retinopathy, and indeed that it is not effective at the capillarylevel.

Aminoguanidine is a compound having a somewhat similar structure to4GAB, which has been proposed for the prevention of diabeticcomplications. Aminoguanidine may suppress advanced glycosylationend-products, and has been reported to prevent the capillary lesions ofretinopathy in diabetic rats.

SUMMARY OF THE INVENTION

According to the present invention, 4GAB or a physiologically-acceptablesalt thereof, is used for the purposes of arteriolar dilatation. 4GAB istherefore useful in the regulation of blood flow, and in the preventionand/or management of complications that are observed, often indiabetics, in tissues such as the kidneys, nerves, skin and Islets ofLangerhans. It may also have utility in treating male impotence (indiabetic cases, perhaps in cases of senile impotence, and moregenerally), by facilitating penile erection.

DESCRIPTION OF THE INVENTION

Without wishing to be bound by theory, it appears that 4GAB exerts itsdilatatory effect through NO release through small vessels, arterioles.4GAB is a compound in the metabolic sequence from the brain constituentGABA to arginine which itself is a precursor of NO. The metabolism of4GAB to arginine is controlled by enzymes that may be glucose-related.

This mechanism explains the absence of effect on retinopathy and perhapsalso the effects that have previously been associated with theadministration of 4GAB. The mechanism and the results presented belowshow that 4GAB is of particular utility in treating or preventing renalcomplications, neuropathy and autonomic neuropathy (possibly byaffecting neuronal nutrition) and providing improved circulation, e.g.in dementias or in counteracting the reduced circulation usuallyobserved in old age.

In both diabetic and non-diabetic patients, 4GAB may act as ananti-neuropathic and, at least in some cases, as a protrophic agent. Forexample, it may reverse peripheral neuropathy and also incontinenceassociated with lack of suppression of urination. Infants lack controlthrough a regular cycle of release, and a similar condition can developin adult life and particularly in old age.

The possible mechanism and effects of 4GAB have been confirmed by theinjection of radioactively-labelled 4GAB into mice. Radioautographsshowed that almost all the injected 4GAB was immediately taken up in thewalls of blood vessels. No specific localisation in any of the bodyorgans concerned with glucose metabolism, e.g. the liver, kidneys andmuscles, could be recognised.

4GAB can be produced simply and inexpensively. It is essentiallynon-toxic. It can be formulated with physiologically-acceptable carriersor excipients of any conventional type, depending on the mode ofadministration. Formulations, modes of administration and dosages areexemplified in GB-A-1195200 and U.S. Pat. No. 3,639,628, the contents ofwhich are herein incorporated by reference.

The following Examples illustrate the utility of 4GAB.

EXAMPLE 1

A subject who was healthy but whose peripheral circulation was poor tooktablets of 4GAB for a month. He reported a return of libido and penileerections, and that his feet were warmer to the touch.

EXAMPLE 2

Before treatment with 4GAB, a diabetic patient had a high fixed pulserate. When he performed the Valsalva manoeuvre, it was obvious that hehad lost the variations of pulse rate associated with slow deepbreathing and forced breathing. This was presumably due to a specificdiabetic autonomic neuropathic effect inhibiting the vagus nerveimpulses to his cardiovascular system. An electrocardiogram of thepatient showed the fast fixed pulse rate and, more importantly, afailure for any alteration of pulse rate as a result of deep breathing.

The patient was given 500 mg of 4GAB by mouth three times a day for twoweeks. At the end of the treatment, his resting pulse had fallen from afixed rate of 95 to just over 80 per minute and there were smallvariations in his pulse rate during deep breathing.

EXAMPLE 3

A group of 8 diabetics with fast resting pulses was tested. The pulseswere monitored both at rest and during the Valsalva manoeuvre.

Administration of 4GAB was associated with a clear reduction in theresting pulse rate, which returned to earlier levels within 2-3 monthsof ceasing therapy. It was also observed that the patients were broughtunder control after 2-3 months by repeating the therapy. 7 of the 8subjects showed an improvement in the sinus arrhythmia reflex, i.e. areturn of pulse variation.

EXAMPLE 4

A patient whose diabetes had been treated over 30 years with insulinsuffered from numbness in her feet. After 1-2 years of therapy with4GAB, her requirement for insulin was reduced, and the patient reportedsensations of feeling in her previously numb feet and also that sweatinghad returned in the skin of her lower legs. The administration of 4GABdid not prevent deterioration in her vision and the occurrence ofretinal haemorrhages from her diabetic retinopathy. These observationsare consistent with the theory that 4GAB affects the blood flow to theIslets of Langerhans.

EXAMPLE 5

A long-term diabetic patient was suffering from mild diabeticneuropathy, albumin urea and a succession of mild renal infections. Hertreatment was augmented by the adminstration of 500 mg 4GAB per day, intablet form. The 4GAB had a sparing effect on her insulin requirement.The clinical progress of her retinopathy was not affected, but theprogress of her renal disease was, in contrast, remarkably slow. In theearly stages of the augmented treatment, her glomerular filtration rate(GFR) was 28-30. 10 years later, her GFR was recorded as 40 (without anycorresponding rise in blood urea levels).

I claim:
 1. A method for improving blood circulation in a mammal orhuman patient in need of improved blood circulation which comprisesadministering to said patient an effective mount of4-guanidinobutyramide, or a physiologically acceptable salt thereof, toimprove said blood circulation.
 2. The method, according to claim 1,wherein said mammal or human patient is suffering from complicationsassociated with inadequate blood circulation in the kidneys, nerves,skin, or Islets of Langerhans.
 3. The method, according to claim 1,wherein said human patient is in need of the prevention or treatment ofmale impotence.
 4. The method, according to claim 1, wherein said mammalor human patient is diabetic.
 5. The method, according to claim 4;wherein said human patient is treated with about 500 mg of4-guanidinobutyramide per day in tablet form for a period of timesufficient to improve blood circulation.
 6. The method, according toclaim 1, wherein said 4-guanidinobutyramide, or a physiologicallyacceptable salt thereof, is administered with a physiologicallyacceptable carrier or excipient.